Abstract
Oligomeric forms of amyloid-forming proteins are believed to be the principal initiating bioactive species in many neurodegenerative disorders, including Alzheimer's disease (AD). Amyloid-β (Ab) oligomers are implicated in AD-associated phosphorylation and aggregation of the microtubule-associated protein tau. To investigate the specific molecular pathways activated by different assemblies, we isolated various forms of Aβ from Tg2576 mice, which are a model for AD. We found that Aβ∗56, a 56-kDa oligomer that is detected before patients develop overt signs of AD, induced specific changes in neuronal signaling. In primary cortical neurons, Aβ∗56 interacted with N-methyl-D-aspartate receptors (NMDARs), increased NMDAR-dependent Ca2+ influx, and consequently increased intracellular calcium concentrations and the activation of Ca2+-dependent calmodulin kinase IIa (CaMKIIa). In cultured neurons and in the brains of Tg2576 mice, activated CaMKIIa was associated with increased site-specific phosphorylation and missorting of tau, both of which are associated with AD pathology. In contrast, exposure of cultured primary cortical neurons to other oligomeric Aβ forms (dimers and trimers) did not trigger these effects. Our results indicate that distinct Aβ assemblies activate neuronal signaling pathways in a selective manner and that dissecting the molecular events caused by each oligomer may inform more effective therapeutic strategies. 2017
| Original language | English (US) |
|---|---|
| Article number | aal2021 |
| Journal | Science signaling |
| Volume | 10 |
| Issue number | 478 |
| DOIs | |
| State | Published - May 9 2017 |
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The amyloid-β oligomer Aβ∗56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation. / Amar, Fatou; Sherman, Mathew A; Rush, Travis; Larson, Megan; Boyle, Gabriel; Chang, Liu; Götz, Jürgen; Buisson, Alain; Lesne, Sylvain E.
In: Science signaling, Vol. 10, No. 478, aal2021, 09.05.2017.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The amyloid-β oligomer Aβ∗56 induces specific alterations in neuronal signaling that lead to tau phosphorylation and aggregation
AU - Amar, Fatou
AU - Sherman, Mathew A
AU - Rush, Travis
AU - Larson, Megan
AU - Boyle, Gabriel
AU - Chang, Liu
AU - Götz, Jürgen
AU - Buisson, Alain
AU - Lesne, Sylvain E
PY - 2017/5/9
Y1 - 2017/5/9
N2 - Oligomeric forms of amyloid-forming proteins are believed to be the principal initiating bioactive species in many neurodegenerative disorders, including Alzheimer's disease (AD). Amyloid-β (Ab) oligomers are implicated in AD-associated phosphorylation and aggregation of the microtubule-associated protein tau. To investigate the specific molecular pathways activated by different assemblies, we isolated various forms of Aβ from Tg2576 mice, which are a model for AD. We found that Aβ∗56, a 56-kDa oligomer that is detected before patients develop overt signs of AD, induced specific changes in neuronal signaling. In primary cortical neurons, Aβ∗56 interacted with N-methyl-D-aspartate receptors (NMDARs), increased NMDAR-dependent Ca2+ influx, and consequently increased intracellular calcium concentrations and the activation of Ca2+-dependent calmodulin kinase IIa (CaMKIIa). In cultured neurons and in the brains of Tg2576 mice, activated CaMKIIa was associated with increased site-specific phosphorylation and missorting of tau, both of which are associated with AD pathology. In contrast, exposure of cultured primary cortical neurons to other oligomeric Aβ forms (dimers and trimers) did not trigger these effects. Our results indicate that distinct Aβ assemblies activate neuronal signaling pathways in a selective manner and that dissecting the molecular events caused by each oligomer may inform more effective therapeutic strategies. 2017
AB - Oligomeric forms of amyloid-forming proteins are believed to be the principal initiating bioactive species in many neurodegenerative disorders, including Alzheimer's disease (AD). Amyloid-β (Ab) oligomers are implicated in AD-associated phosphorylation and aggregation of the microtubule-associated protein tau. To investigate the specific molecular pathways activated by different assemblies, we isolated various forms of Aβ from Tg2576 mice, which are a model for AD. We found that Aβ∗56, a 56-kDa oligomer that is detected before patients develop overt signs of AD, induced specific changes in neuronal signaling. In primary cortical neurons, Aβ∗56 interacted with N-methyl-D-aspartate receptors (NMDARs), increased NMDAR-dependent Ca2+ influx, and consequently increased intracellular calcium concentrations and the activation of Ca2+-dependent calmodulin kinase IIa (CaMKIIa). In cultured neurons and in the brains of Tg2576 mice, activated CaMKIIa was associated with increased site-specific phosphorylation and missorting of tau, both of which are associated with AD pathology. In contrast, exposure of cultured primary cortical neurons to other oligomeric Aβ forms (dimers and trimers) did not trigger these effects. Our results indicate that distinct Aβ assemblies activate neuronal signaling pathways in a selective manner and that dissecting the molecular events caused by each oligomer may inform more effective therapeutic strategies. 2017
UR - http://www.scopus.com/inward/record.url?scp=85019231994&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019231994&partnerID=8YFLogxK
U2 - 10.1126/scisignal.aal2021
DO - 10.1126/scisignal.aal2021
M3 - Article
C2 - 28487416
AN - SCOPUS:85019231994
VL - 10
JO - Science Signaling
JF - Science Signaling
SN - 1937-9145
IS - 478
M1 - aal2021
ER -